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Human farnesyl pyrophosphate synthase inhibition by nitrogen bisphosphonates: a 3D-QSAR study

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Abstract

We report the results of a comparative molecular field analysis and comparative molecular similarity index analysis of the human farnesyl pyrophosphate synthase (FPPS) inhibition by nitrogen bisphosphonates (NBPs) taking into account their time-dependent inhibition efficacies. The 3D-QSAR models obtained provide steric, electrostatic and hydrophobic contour maps consistent with the interactions into the active site of human FPPS observed in available crystallographic structures. Furthermore, the 3D-QSAR models obtained provide accurately IC50 values of the NBPs of the training set. The predictive ability of these 3D-QSAR models was found to rely on the choice of biologically active conformations of the target molecules and on a careful examination of the protonation status of the NBPs in the training set. The best models obtained can be useful to predict biological values of a high number of NBPs that have been used for the treatment of different diseases as potential inhibitors of the activity of the FPPS enzyme.

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  1. Departament de Química, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, 07122, Spain

    David Fernández, Joaquín Ortega-Castro & Juan Frau

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  1. David Fernández
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  2. Joaquín Ortega-Castro
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  3. Juan Frau
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Correspondence to Juan Frau.

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Fernández, D., Ortega-Castro, J. & Frau, J. Human farnesyl pyrophosphate synthase inhibition by nitrogen bisphosphonates: a 3D-QSAR study. J Comput Aided Mol Des 27, 739–754 (2013). https://doi.org/10.1007/s10822-013-9674-2

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